{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T19:47:07Z","timestamp":1778960827805,"version":"3.51.4"},"reference-count":29,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,3,23]],"date-time":"2018-03-23T00:00:00Z","timestamp":1521763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH\/NICHD","award":["R03HD081135"],"award-info":[{"award-number":["R03HD081135"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2018,4,17]]},"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn morbidity and mortality. CDH is considered to be a multifactorial disease, with strong evidence implicating genetic factors. Although recent studies suggest the biological role of deleterious germline de novo variants, the effect of gene variants specific to the diaphragm remains unclear, and few single genes have been definitively implicated in human disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed genome sequencing on 16 individuals with CDH and their unaffected parents, including 10 diaphragmatic samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We did not detect damaging somatic mutations in diaphragms, but identified germline heterozygous de novo functional mutations of 14 genes in nine patients. Although the majority of these genes are not known to be associated with CDH, one patient with CDH and cardiac anomalies harbored a frameshift mutation in <jats:italic>NR2F2<\/jats:italic> (aka <jats:italic>COUP\u2010TFII<\/jats:italic>), generating a premature truncation of the protein. This patient also carried a missense variant predicted to be damaging in <jats:italic>XIRP2<\/jats:italic> (aka Myomaxin), a transcriptional target of <jats:italic>MEF2A<\/jats:italic>. Both <jats:italic>NR2F2<\/jats:italic> and <jats:italic>MEF2A<\/jats:italic> map to chromosome 15q26, where recurring de novo deletions and unbalanced translocations have been observed in CDH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Somatic variants are not common in CDH. To our knowledge, this is the second case of a germline de novo frameshift mutation in <jats:italic>NR2F2<\/jats:italic> in CDH. Since <jats:italic>NR2F2<\/jats:italic> null mice exhibit a diaphragmatic defect, and <jats:italic>XIRP2<\/jats:italic> is implicated in cardiac development, our data suggest the role of these two variants in the etiology of CDH, and possibly cardiac anomalies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.1223","type":"journal-article","created":{"date-parts":[[2018,3,23]],"date-time":"2018-03-23T13:26:37Z","timestamp":1521811597000},"page":"610-617","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia"],"prefix":"10.1002","volume":"110","author":[{"given":"Nori","family":"Matsunami","sequence":"first","affiliation":[{"name":"Departments of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hari","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Neonatology) University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Baird","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Stevens","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice L.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas C.","family":"Barnhart","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Primary Children's Medical Center University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carrie","family":"Rau","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Neonatology) University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9171-7848","authenticated-orcid":false,"given":"Marcia L.","family":"Feldkamp","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Medical Genetics) University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley A.","family":"Yoder","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Neonatology) University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark F.","family":"Leppert","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. Joseph","family":"Yost","sequence":"additional","affiliation":[{"name":"Department of Neurobiology &amp; Anatomy and Department of Pediatrics University of Utah School of Medicine Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2807-8606","authenticated-orcid":false,"given":"Luca","family":"Brunelli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Neonatology) University of Utah School of Medicine Salt Lake City Utah"},{"name":"Department of Pediatrics (Neonatology) University of Nebraska Medical Center and Children's Hospital &amp; Medical Center Omaha NE"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,3,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.03.007"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35664"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000322422"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2005.03.025"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37830"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/513442"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603244200"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1086\/429842"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22376"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1774-y"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12395"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3250"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3468(95)90565-0"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20735"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00000624"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016-2043"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr407"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0810-575"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.1106"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22225"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2014.04.012"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2012.04.002"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2012.12.007"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507832102"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv196"}],"container-title":["Birth Defects Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdr2.1223","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.1223","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T17:05:02Z","timestamp":1695575102000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdr2.1223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,23]]},"references-count":29,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2018,4,17]]}},"alternative-id":["10.1002\/bdr2.1223"],"URL":"https:\/\/doi.org\/10.1002\/bdr2.1223","archive":["Portico"],"relation":{},"ISSN":["2472-1727","2472-1727"],"issn-type":[{"value":"2472-1727","type":"print"},{"value":"2472-1727","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,23]]},"assertion":[{"value":"2017-12-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}